Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection

Abstract

Chronic hepatitis B virus (HBV) infection remains to be a substantial global burden, especially for end-stage liver diseases. It is well accepted that HBV-specific T and B cells are essential for controlling HBV infection. Toll-like receptors (TLRs) represent one of the major first-line antiviral defenses through intracellular signaling pathways that induce antiviral inflammatory cytokines and interferons, thereby shaping adaptive immunity. However, HBV has evolved strategies to counter TLR responses by suppressing the expression of TLRs and blocking the downstream signaling pathways, thus limiting HBV-specific adaptive immunity and facilitating viral persistence. Recent studies have stated that stimulation of the TLR signaling pathway by different TLR agonists strengthens host innate immune responses and results in suppression of HBV replication. In this review, we will discuss how TLR-mediated responses shape HBV-specific adaptive immunity as demonstrated in different experimental models. This information may provide important insight for HBV functional cure based on TLR agonists as immunomodulators.

Keywords: T cell response; Toll-like receptor; adaptive immunity; hepatitis B virus; innate immunity.

Figure 1

TLRs regulate HBV-specific T-cell responses. TLRs are expressed in T cells, hepatocytes, and hepatic non-parenchymal cells, including LSECs, KCs, and DCs. TLRs may directly shape the T-cell response as costimulatory molecules. Stimulation of TLRs by their ligands leads to the activation of the downstream MyD88/TRIF-dependent signaling pathway in hepatic non-parenchymal cells and promotes the maturation of these cells, thus promoting antigen presentation to T cells and the production of IFNs, proinflammatory cytokines, and chemokines. IFNs exert antiviral effects against HBV in infected hepatocytes. Chemokines and inflammatory cytokines recruit DCs, macrophages, and specific T cells into the liver and promote HBV-specific T-cell activation and proliferation. Activated CLTs then kill infected hepatocytes. CTL, cytotoxic T cell; DC, dendritic cell; HBV, hepatitis B virus; IFN, interferon; LSEC, liver sinusoidal endothelial cell; KC, Kupffer cell; TLR, Toll-like receptor.